ChloroquineV1, Pmc, Curation, bibRecord, 000921

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Identifieur interne : 000921 ( Pmc/Curation ); précédent : 000920; suivant : 000922

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Auteurs : Jean Christopher Chamcheu [États-Unis] ; Tithi Roy [États-Unis] ; Mohammad Burhan Uddin [États-Unis] ; Sergette Banang-Mbeumi [États-Unis] ; Roxane-Cherille N. Chamcheu [États-Unis] ; Anthony L. Walker [États-Unis] ; Yong-Yu Liu [États-Unis] ; Shile Huang [États-Unis]

Source :

Cells [ 2073-4409 ] ; 2019.

RBID : PMC:6721560

Abstract

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721560

DOI: 10.3390/cells8080803
PubMed: 31370278
PubMed Central: 6721560

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<author><name sortKey="Walker, Anthony L" sort="Walker, Anthony L" uniqKey="Walker A" first="Anthony L." last="Walker">Anthony L. Walker</name>
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<front><div type="abstract" xml:lang="en"><p>The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.</p>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id>
<journal-id journal-id-type="iso-abbrev">Cells</journal-id>
<journal-id journal-id-type="publisher-id">cells</journal-id>
<journal-title-group><journal-title>Cells</journal-title>
</journal-title-group>
<issn pub-type="epub">2073-4409</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31370278</article-id>
<article-id pub-id-type="pmc">6721560</article-id>
<article-id pub-id-type="doi">10.3390/cells8080803</article-id>
<article-id pub-id-type="publisher-id">cells-08-00803</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3927-5664</contrib-id>
<name><surname>Chamcheu</surname>
<given-names>Jean Christopher</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
<xref rid="c1-cells-08-00803" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Roy</surname>
<given-names>Tithi</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9665-7442</contrib-id>
<name><surname>Uddin</surname>
<given-names>Mohammad Burhan</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Banang-Mbeumi</surname>
<given-names>Sergette</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
<xref ref-type="aff" rid="af2-cells-08-00803">2</xref>
<xref ref-type="aff" rid="af3-cells-08-00803">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chamcheu</surname>
<given-names>Roxane-Cherille N.</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7552-5192</contrib-id>
<name><surname>Walker</surname>
<given-names>Anthony L.</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Yong-Yu</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00803">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3239-1072</contrib-id>
<name><surname>Huang</surname>
<given-names>Shile</given-names>
</name>
<xref ref-type="aff" rid="af4-cells-08-00803">4</xref>
<xref ref-type="aff" rid="af5-cells-08-00803">5</xref>
</contrib>
</contrib-group>
<aff id="af1-cells-08-00803"><label>1</label>
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA</aff>
<aff id="af2-cells-08-00803"><label>2</label>
Division for Research and Innovation, POHOFI Inc., P.O. Box 44067, Madison, WI 53744, USA</aff>
<aff id="af3-cells-08-00803"><label>3</label>
School of Nursing and Allied Health Sciences, Louisiana Delta Community College, Monroe, LA 71203, USA</aff>
<aff id="af4-cells-08-00803"><label>4</label>
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA</aff>
<aff id="af5-cells-08-00803"><label>5</label>
Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA</aff>
<author-notes><corresp id="c1-cells-08-00803"><label>*</label>
Correspondence: <email>chamcheu@ulm.edu</email>
; Tel.: +1-318-342-6820; Fax: +1-318-342-1737</corresp>
</author-notes>
<pub-date pub-type="epub"><day>31</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>8</month>
<year>2019</year>
</pub-date>
<volume>8</volume>
<issue>8</issue>
<elocation-id>803</elocation-id>
<history><date date-type="received"><day>07</day>
<month>7</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>29</day>
<month>7</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.</p>
</abstract>
<kwd-group><kwd>PI3K</kwd>
<kwd>Akt</kwd>
<kwd>mTOR</kwd>
<kwd>skin cancers</kwd>
<kwd>phytochemicals</kwd>
<kwd>melanoma</kwd>
<kwd>basal cell carcinoma</kwd>
<kwd>squamous cell carcinoma</kwd>
<kwd>Merkel cell carcinoma</kwd>
<kwd>targeted therapy</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="cells-08-00803-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Schematic representation of the cross section of the skin. The skin is composed of epidermis, dermis, and hypodermis. The dermis supports and provides nourishment to the overlying epidermis through its constituent blood and lymphatic vessels. The skin also comprises sensory elements, various resident cell types like fibroblasts, macrophages, and lymphocytes. The ectodermally derived appendage such as sweat glands, sebaceous glands, and hair follicles arises as an invagination of the epidermis into the dermis. The epidermal stem cells are found in the bulge region of the hair follicles, in the basal layer of the interfollicular epidermis, and to some extent the sebaceous glands.</p>
</caption>
<graphic xlink:href="cells-08-00803-g001"></graphic>
</fig>
<fig id="cells-08-00803-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Schematic representation of the structure of the epidermis and papillary dermis. This stratified epithelium consists of basal, spinous, granular, lucidum, and stratum corneum layers. The basal layer contains the stem cells that sit or attach to the basal lamina via hemidesmosomes. In normal epidermis, basal keratinocytes express K5, K14, and integrins. The suprabasal and differentiating layers of keratinocytes are committed to differentiation, expressing K1, K10, and other markers, like filaggrin and loricrin. Other resident epidermal cell types include Melanocytes, Langerhans cells, and Merkel cells. The ultraviolet rays (UVR) from the sun penetrate the atmosphere and the different layers of the skin. UVC with the greatest energy photons (shorter wavelengths) is totally absorbed by the ozone layer while UVB with intermediate energy photons (wavelengths) that damage DNA in epidermal cells penetrates the upper layers of the epidermis. UVA with low energy photons (longer wavelengths) penetrates deeper into the upper dermis causing damage to collagen and elastic tissue, even skin cancers and other skin manifestations.</p>
</caption>
<graphic xlink:href="cells-08-00803-g002"></graphic>
</fig>
<fig id="cells-08-00803-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Schematic of the domain structure of mTOR showing the <italic>N</italic>
-terminus with two tandem HEAT repeats, followed by a FAT domain (domain shared by PI3K-related protein kinases (PIKK) family members), an FRB domain (FKBP-12-rapamycin-binding site), a kinase catalytic domain, a repressor domain (RD), and a FAT C terminus domain located at the <italic>C</italic>
-terminus of the protein. The FRB domain forms a deep hydrophobic cleft that serves as the high-affinity binding site for the inhibitory complex FKBP12-rapamycin [<xref rid="B52-cells-08-00803" ref-type="bibr">52</xref>
].</p>
</caption>
<graphic xlink:href="cells-08-00803-g003"></graphic>
</fig>
<fig id="cells-08-00803-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Schematic illustration of the PI3K/Akt/mTOR signaling pathway. Arrows represent activation, whereas bars represent inhibition [<xref rid="B50-cells-08-00803" ref-type="bibr">50</xref>
]. Upon receptor activation, insulin receptor substrate (IRS) activates phosphatidylinositol 3-kinase (PI3K), which is in turn phosphorylated to generate phosphatidylinositol [3,4,5]-trisphosphate (PIP3). Phosphatase and tensin homolog (PTEN) can dephosphorylate PIP3 to regulate the pathway activity. AKT is activated through the binding of PIP3 to its amino terminal, pleckstrin homology (PH) domain (stripped), which then promotes the translocation of AKT to the plasma membrane, where the carboxyl terminal T308 is phosphorylated by phosphoinositide-dependent kinase-1 (PDK1), and S473 is phosphorylated by mTORC2. AKT regulates several cellular processes such as survival and cell proliferation, through a variety of downstream proteins like glycogen synthase kinase 3-beta (GSK-3β), Forkhead Box O (FOXO), amid others (not shown). AKT is able to directly phosphorylate and thus inactivates the 40 kDa proline-rich protein (PRAS40), relieving the suppressive regulation on mTORC1 activity. Furthermore, AKT can phosphorylate and inactivate the tuberous sclerosis (TSC) tumor suppressor protein complex that acts as a GTPase-activating protein (GAP) for the RAS homolog enriched in brain (Rheb) small G protein to regulate its activity. Retention of the Rheb-GTP bound form activates mTOR, which is comprised of two main complexes that are associated with diverse proteins such as Raptor, mLST8, PRAS40 and Deptor for complex I (mTORC1), and Rictor, mLST8, Deptor, mSin1 and Protor for complex II (mTORC2). mTORC1 is regulated by a variety of environmental signals mediated via several proteins including REDD1/2 (regulated in development and DNA damage responses 1/2), AMP-activated protein kinase (AMPK), among others. mTORC1 phosphorylates downstream S6K1 (p70S6 Kinase 1) and modulates the eukaryotic initiation factor 4E-binding protein (4E-BP1), which discharges it from hindering eIF4E, and enabling 40S ribosomal subunit to be recruited to mRNAs, leading to the initiation of protein translation. S6K also phosphorylates ribosomal protein S6 that is also involved in translational regulation by the 40S ribosomal subunit. By contrast, the regulation of mTORC2 is still under investigation, but it is known to be regulated by growth factors. mTORC2 phosphorylates distinct groups of proteins, enabling the regulation of actin cytoskeleton and migration via activating protein kinase C α (PKC-α), small GTPases (Rhoa, Rac1 and Cdc42), and focal adhesion proteins, such as focal adhesion kinase (FAK) and paxillin. Essentially, the activation of the RAS-RAF-MEK-ERK-RSK pathway mediated by growth factor is another mechanism of regulated crosstalk with the PI3K/AKT/mTOR signaling pathway.</p>
</caption>
<graphic xlink:href="cells-08-00803-g004"></graphic>
</fig>
<table-wrap id="cells-08-00803-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00803-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>List of reported lead synthetic compounds targeting mTOR, PI3K, and Akt signaling pathway in various skin cancers.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Lead Compound(s)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Protein Target(s)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Skin Cancer Type</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound Structure</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Everolimus (RAD-001)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma, Basal Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i001.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B92-cells-08-00803" ref-type="bibr">92</xref>
,<xref rid="B93-cells-08-00803" ref-type="bibr">93</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Erufosine </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral Squamous Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-cells-08-00803" ref-type="bibr">94</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GDC-0084</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, mTOR, Akt</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">cutaneous Squamous Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B95-cells-08-00803" ref-type="bibr">95</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Isoselenocyanate-4</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i002.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B96-cells-08-00803" ref-type="bibr">96</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MLN0128 (Sapanisertib)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma<break></break>
Merkel Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i003.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B97-cells-08-00803" ref-type="bibr">97</xref>
,<xref rid="B98-cells-08-00803" ref-type="bibr">98</xref>
,<xref rid="B99-cells-08-00803" ref-type="bibr">99</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NVP-BEZ235</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma <break></break>
Merkel Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i004.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B100-cells-08-00803" ref-type="bibr">100</xref>
,<xref rid="B101-cells-08-00803" ref-type="bibr">101</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NC1 domain of collagen Type XIX [NC1(XIX)] </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR, FAK</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B89-cells-08-00803" ref-type="bibr">89</xref>
,<xref rid="B90-cells-08-00803" ref-type="bibr">90</xref>
,<xref rid="B91-cells-08-00803" ref-type="bibr">91</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PBISe</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Invasive metastatic Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i005.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B102-cells-08-00803" ref-type="bibr">102</xref>
] </td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rapamycin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3k, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma, Esophageal squamous cell carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i006.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B77-cells-08-00803" ref-type="bibr">77</xref>
,<xref rid="B78-cells-08-00803" ref-type="bibr">78</xref>
,<xref rid="B103-cells-08-00803" ref-type="bibr">103</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SKLB-M8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B87-cells-08-00803" ref-type="bibr">87</xref>
,<xref rid="B88-cells-08-00803" ref-type="bibr">88</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI-103</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B104-cells-08-00803" ref-type="bibr">104</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Perifosine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Metastatic Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B105-cells-08-00803" ref-type="bibr">105</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tazarotene</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IGFR, PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Basal cell carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B106-cells-08-00803" ref-type="bibr">106</xref>
,<xref rid="B107-cells-08-00803" ref-type="bibr">107</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Temsirolimus</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Metastatic melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i007.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B108-cells-08-00803" ref-type="bibr">108</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WYE-354</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Merkel cell carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B109-cells-08-00803" ref-type="bibr">109</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VS-5584</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K and mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B67-cells-08-00803" ref-type="bibr">67</xref>
,<xref rid="B84-cells-08-00803" ref-type="bibr">84</xref>
,<xref rid="B85-cells-08-00803" ref-type="bibr">85</xref>
,<xref rid="B86-cells-08-00803" ref-type="bibr">86</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Itraconazole</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K and mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma<break></break>
Basal Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B110-cells-08-00803" ref-type="bibr">110</xref>
,<xref rid="B111-cells-08-00803" ref-type="bibr">111</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LY3023414</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K/mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cutaneous Basal Cell Carcinoma, cutaneous Squamous Cell Carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B112-cells-08-00803" ref-type="bibr">112</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ku-0063794</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTORC1 and mTORC2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BRAF-Mutant Melanoma in combination with MEK inhibitory agents<break></break>
Merkel cell carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i008.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B113-cells-08-00803" ref-type="bibr">113</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="cells-08-00803-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00803-t002_Table 2</object-id>
<label>Table 2</label>
<caption><p>List of reported lead natural dietary compounds and extracts targeting mTOR, PI3K, and Akt signaling pathway in various skin cancers.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Lead Compound (s)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Protein Targets</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Skin Cancer Type</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound Structure</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acacetin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Malignant Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i009.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B124-cells-08-00803" ref-type="bibr">124</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bee Venom Melittin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B129-cells-08-00803" ref-type="bibr">129</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Capsaicin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, Rac1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i010.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B126-cells-08-00803" ref-type="bibr">126</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i011.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B142-cells-08-00803" ref-type="bibr">142</xref>
,<xref rid="B143-cells-08-00803" ref-type="bibr">143</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Epigallocatechin-3 (EGCG)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i012.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B148-cells-08-00803" ref-type="bibr">148</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Evodiamine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i013.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B127-cells-08-00803" ref-type="bibr">127</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fisetin</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i014.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B68-cells-08-00803" ref-type="bibr">68</xref>
,<xref rid="B139-cells-08-00803" ref-type="bibr">139</xref>
,<xref rid="B140-cells-08-00803" ref-type="bibr">140</xref>
,<xref rid="B141-cells-08-00803" ref-type="bibr">141</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Isoliquiritigenin </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTORC2, Akt,<break></break>
GSK-3β</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma cachexia</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i015.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B128-cells-08-00803" ref-type="bibr">128</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Harmine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt, mTOR and ERK1/2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i016.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B131-cells-08-00803" ref-type="bibr">131</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Obatoclax</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B133-cells-08-00803" ref-type="bibr">133</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Panduratin A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i017.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B130-cells-08-00803" ref-type="bibr">130</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prodigiosin </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B133-cells-08-00803" ref-type="bibr">133</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Resveratrol</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i018.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B46-cells-08-00803" ref-type="bibr">46</xref>
,<xref rid="B144-cells-08-00803" ref-type="bibr">144</xref>
,<xref rid="B145-cells-08-00803" ref-type="bibr">145</xref>
,<xref rid="B146-cells-08-00803" ref-type="bibr">146</xref>
] </td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sinomenine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K, Akt, mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i019.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B132-cells-08-00803" ref-type="bibr">132</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Honokiol</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma,<break></break>
Oral squamous cell carcinoma</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><inline-graphic xlink:href="cells-08-00803-i020.jpg"></inline-graphic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B63-cells-08-00803" ref-type="bibr">63</xref>
,<xref rid="B147-cells-08-00803" ref-type="bibr">147</xref>
,<xref rid="B151-cells-08-00803" ref-type="bibr">151</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nexrutine<sup>R</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PI3K/Akt/mTOR</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Melanoma </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B149-cells-08-00803" ref-type="bibr">149</xref>
,<xref rid="B150-cells-08-00803" ref-type="bibr">150</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
</record>

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Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

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